The inherent pharmacokinetic properties of the digitalis glycosides digoxin and digitoxin are less than optimal. Digitoxin has a very long elimination half-life (mean 7 to 8 days), while the elimination and myocardial distribution of digoxin are altered by changes in renal function, and its absorption from the gastrointestinal tract is inefficient. This proposal is designed to investigate two of these problems using the dog as an animal model. The aim of the initial study is the identification of a cardiac glycoside with more favorable pharmacokinetic properties than either digoxin or digitoxin. A glycoside with the absorption properties of digitoxin, with elimination and distribution characteristics which are less dependent on renal function than digoxin, and with a half-life similar to digoxin is considered to be ideal. The mono- and bisdigitoxosides of digitoxigenin are two cardioactive metabolites of digitoxin which are proposed as candidates to meet these criteria. The absorption, distribution and elimination characteristics of these two metabolites will be compared to digitoxin in the healthy and azotemic dog. The second study is designed to investigate the influence of altered renal function on the myocardial distribution of and response to digoxin. Digoxin will be infused to a predetermined steady-state plasma concentration in dogs with normal renal function and surgically induced renal failure. The binding of digoxin to Na, K-ATPase, generally assumed to be the digitalis "receptor", and myocardial contractility will be determined in both groups of animals in an attempt to gain some insight into the potential significance of renal failure on digoxin plasma concentration-response relationships.